Category Archives: C diff Treatments

A tapered and pulsed regimen with vancomycin — with diligent follow-up — can achieve significant cure rates in recurrent Clostridium difficile (C. difficile) infected patients, according to a new study.

Researchers from Loyola Medicine retrospectively studied 100 vancomycin taper and pulse treatment patients treated for recurrent C. difficile infection between January 1, 2009 and December 31, 2014. Their clinic, the study authors wrote, has been a referral center for the infection for the past decade.

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However, despite the guidelines for treatment of recurrent C. difficile infection being not too different than recurrent episodes – except for the use of vancomycin when the case is severe – there have not been many studies on this vancomycin taper and pulsed dosing.

The researchers observed that after a referral, the confirmed recurrent C. difficile patients were treated with a vancomycin taper and pulse regimen: a taper of vancomycin to once-daily, followed by alternate day dosing; or once-daily followed by alternate day dosing; followed by every third day, for at least 2 weeks. After this regimen, all patients had 90-day follow-up documentation.

On average, the patients in the clinic were on their third C. difficile diarrhea episode. Half of the patients had also received a standard course of vancomycin, while another third had received some type of vancomycin taper regimen, the researchers said.

Despite the fact that many of these patients were a “treatment experienced” population, 75% of the patients who received a supervised vancomycin taper and pulsed regimen achieved a cure, study author Stuart Johnson MD, . He added that the results were further improved for patients who received the expended pulse phase: 81% achieved a cure.

“The findings were not unexpected to us, but I think that many clinicians will be surprised how well a deliberate, prolonged vancomycin taper and pulse regimen – with careful follow up – works,” Johnson said.

There were no significant differences among the patients in terms of gender, age, concomitant antibiotics, proton pump inhibitor use, histamine receptor-2 blocker use, or patients with a regimen greater than 10 weeks in length, the researchers continued.

The researchers added that their finding of improved cure rates with alternate-day dosing plus every third day dosing over strictly alternate-day dosing is consistent with the hypothesis that pulsed dosing can promote a cyclical decrease in spore burden, they wrote. This can also permit the resetting of normal microbiota in the gut.

Johnson concluded that the clinical implications of the study show most recurrent C. difficile patients do not need fecal microbiota transplant (FMT).

“FMT has received an enormous amount of press and this procedure is now widely available throughout the US,” Johnson said. “FMT is attractive because it addresses one of the primary mechanisms involved with recurrent C. difficile infection, a marked disruption of the resident bacteria that populate the intestine and provide an important host defense against C. difficile.

Although physicians screen donor feces for “known pathogens,” not all is known of the potential complications to come from FMT, Johnson said.

“In addition, it appears that efficacy with a carefully supervised vancomycin taper and pulse regimen compare to that achieved with FMT,” Johnson said.

Ridinilazole treatment more preserving of gut microbiome than fidaxomicin

* Listen In on September 26th 10aPT/1pET www.cdiffradio.com live broadcast with our guests from Summit Therapeutics.

Oxford, UK, 5 September 2017 – Summit Therapeutics plc (NASDAQ: SMMT, AIM: SUMM), the drug discovery and development company advancing therapies for Duchenne muscular dystrophy and Clostridium difficile infection (‘CDI’), today announces positive top-line data from an exploratory Phase 2 clinical trial that support ridinilazole as a highly selective and potent antibiotic product candidate for the treatment of CDI. In the Phase 2 clinical trial, ridinilazole preserved the gut microbiome of CDI patients to a greater extent than the marketed narrow-spectrum antibiotic, fidaxomicin. During the trial’s ten-day treatment period, ridinilazole treatment had markedly less impact on the gut microbiome of trial patients by measures of overall diversity and changes in key bacterial families, when compared to those trial patients dosed with fidaxomicin.

In the trial, ridinilazole and fidaxomicin both reduced the abundance of C. difficile. However, fidaxomicin-treated patients had reduced abundancy of other bacterial families associated with microbiome health. For a number of these bacterial families, the difference between the two treatments was statistically significant. Another measure of microbiome health is alpha diversity as measured by the Simpson’s Diversity Index. There was a greater reduction in alpha-diversity during fidaxomicin treatment compared with ridinilazole-treated patients. These measures were a key secondary endpoint of the clinical trial and provide additional evidence of ridinilazole’s precision in killing C. difficile while preserving the gut microbiome. The primary endpoint of the trial was safety, as measured by the number of treatment emergent adverse events and serious adverse events. During the trial, no new or unexpected safety signals were identified and ridinilazole was well-tolerated.

“We increasingly recognise the importance of a healthy and diverse gut microbiome for protection against recurrent CDI, which is a major challenge in the management of the disease. These latest clinical findings show ridinilazole better preserved the microbiome of CDI patients than fidaxomicin, the narrowest spectrum antibiotic currently available for CDI,”commented Professor Mark Wilcox, Consultant Microbiologist & Head of Microbiology Research & Development at the Leeds Teaching Hospitals NHS Trust, Professor of Medical Microbiology at the University of Leeds, and Public Health England’s Lead on C. difficile in England. “Further, these microbiome data are very supportive of ridinilazole’s profile as a highly selective antibiotic with the potential to achieve a meaningful improvement in clinical outcomes for CDI patients.”

The exploratory open-label Phase 2 clinical trial enrolled 27 patients aged between 18 and 90 years at trial sites in the US, the UK and the Czech Republic. Patients were randomly assigned to receive either ridinilazole (200mg, twice a day) or fidaxomicin (200mg, twice a day) for ten days. The trial population was unbalanced with more patients randomised to ridinilazole at higher risk of poorer clinical outcomes as measured by ATLAS score, and also with predisposing factors for recurrent CDI.

A secondary endpoint of sustained clinical response (‘SCR’), defined as clinical cure at the end of treatment and no recurrence of CDI within the next 30 days, was achieved in seven of 14 ridinilazole treated patients and six of 13 fidaxomicin treated patients. The trial was not designed for efficacy comparisons due to the small number of patients.

Dr David Roblin, Chief Medical and Operating Officer of Summitadded, “Ridinilazole is a precision antibiotic that is designed to selectively target C. difficile while being highly preserving of the gut microbiome that plays a crucial role in naturally protecting against recurrent CDI. Ridinilazole has now provided evidence of its high selectivity in two complementary clinical trials. The data from our earlier Phase 2 trial showed a greater microbiome preservation of ridinilazole-treated patients compared with the current standard of care, vancomycin, which led to achieving statistical superiority in sustained clinical response. We believe ridinilazole has the potential to become a front-line therapy for CDI and look forward to initiating Phase 3 clinical trials in the first half of 2018.”

More detailed findings from this trial are expected to be presented at an upcoming international infectious disease conference. The results build on positive data from a Phase 2 proof of concept trial of ridinilazole that were published in The Lancet Infectious Diseases in April 2017. Ridinilazole is currently being prepared for Phase 3 clinical trials that are planned to commence in the first half of 2018.

Repeated infection with the bacterium Clostridium difficile (C. difficile, C.diff.), which causes abdominal pain, fever, diarrhea is linked to higher death rates, as well as having a significant impact on health services in terms of cost and hospital beds occupied.

In the first of two presentations at the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) (tomorrow (Saturday), Professor Alistair Leanord, from Glasgow University, UK, will say that in Scotland the extra impact on the health service from C. difficile infections amounted to 10,600 bed days a year. “This is the equivalent to a 30-bed hospital ward being fully occupied all year,” he will say.

He will tell the congress that the (median) average cost of a patient with C. difficile infection was £7,500 (€8,600 approximately) compared to £2,800 (€3,200 approx) for patients with other medical conditions. In Scotland over a one year period, from October 2015 to October 2016, there were 1,150 cases of C. difficile infection in patients aged 15 and over. This cost the National Health Service (NHS) in Scotland a total of £8,650,000. Out of this amount, the additional costs of treating C. difficile infection, over and above the basic cost of a hospital bed and normal medical care, was £1,955,000. The calculations were carried out at Strathclyde University, which is part of the Scottish Healthcare Associated Infection Prevention Institute (SHAIPI) research consortium.

Until now, little has been known about the impact on health service resources from C. difficile infections, and on patients in terms of recurrence of infection, readmission to hospital, length of stay and death rates.

Prof. Leanord and his colleagues in Scotland identified 3,304 patients with C. difficile in Scottish hospitals between 2010 and 2013 and matched them with 9,516 patients who did not have the infection (the control group). Approximately two-thirds of the C. difficile patients acquired the infection in hospital.

They found that patients with C. difficile infection had more than double the risk of dying from any cause within two months of being admitted to hospital; nearly a third of all C. difficile cases (29%) died within two months compared to 14% of patients in the control group. Patients with C. difficile stayed in hospital a (median) average 9.7 days longer than the patients without the infection. Of the 1,712 C. difficile patients who were discharged from hospital within 30 days of the first episode of infection, 59% were readmitted within six months; of the 626 cases discharged more than 30 days after the first episode 53% were readmitted within six months. Few of these re-admissions were directly related to C. difficile infection.

“However, nearly a sixth of patients (14%) who were cured of the initial infection recurred within three months, and nearly one third of them (29%) had a second recurrence within a year,” says Prof. Leanord.

Older people were more vulnerable to a recurrence. Among the patients with C. difficile infection, 22% were aged 85 or over, and patients aged 75 and over had approximately double the risk of a recurrence of the infection compared to those aged under 65. Patients aged between 65-74 had 1.5 times the risk of recurrence compared to younger patients.

Prof. Leanord will conclude: “Having a clear understanding of the nature of C. difficile infections in Scotland will allow the Scottish government to target resources at the most appropriate patients to try to reduce the overall burden of the disease on the health service. Our findings are very likely to be applicable to the rest of the UK and other countries as well.”

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In a second presentation on Saturday, Dr David Enoch, a consultant microbiologist and infection control doctor at the National Infection Service, Public Health England, Cambridge (UK), will report the outcomes of 6,874 patients who had acquired C. difficile infection in hospital between 2002 and 2013 in England. Of these, 1,141 (16.6%) had recurrences of the infection.

“We found that 49% of hospital patients who suffer a recurrent episode of C. difficile infection die within a year, compared to 38% of those who suffer an initial infection only,” he will say. “In addition, 21% of patients with a recurrence suffered other complications as well, such as dehydration, malnourished and sometimes even perforation of the bowel, compared to 18% of patients who did not have a recurrence.”

Dr Enoch estimates that there are approximately 125,000 cases of C. difficile infection in Europe each year, and between 15-30% of these recur. “Cases in the UK have been coming down since 2008, which is most probably due to improvements in antibiotic prescribing and cleaning regimens in hospitals. This is encouraging but more still needs to be done.”

The average age of the patients was 77 and the average length of stay in hospital was 38 days.

“The main risk factor for developing C. difficile infection is prior antibiotic use. These patients are often already ill from some other underlying illness, which explains why they needed antibiotics in the first place. Older people are at greater risk of C. difficile infection as they are often sicker, have other illnesses or conditions, and so need more antibiotics,” he will say.

Dr Enoch continues: “Although much has been done, particularly in the UK, to try to prevent C. difficile infection, strict adherence to antibiotic guidelines by clinicians and thorough cleaning of the hospital environment are crucial in ensuring that patients don’t develop C. difficile infection in the first place. Treatment with a new drug called fidaxomicin has also been shown to reduce the risk of recurrence in patients who are unfortunate enough to develop an infection. However, we still have a lot to learn, particularly about how C. difficile infection occurs in the community, and how best to treat it.”

Treatments for recurrences of C. difficile infection —– include stopping the antibiotic that made the patient susceptible to the infection and starting a different antibiotic that is effective against C. difficile infection. These antibiotics include metronidazole, vancomycin and fidaxomicin. Supportive therapy, such as extra fluids, and surgery in serious or life-threatening cases may also be necessary. Faecal transplantation is emerging as a promising option; this is a process in which the good bacteria that the gut needs but which has been killed off by antibiotics is transplanted into the patient from a healthy donor.

Over the past two decades there has been a sharp rise in the number and severity of infections caused by the bacteria Clostridium difficile (C. diff ) now the most common healthcare-acquired infection in the United States.

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But a new study suggests that the most routinely prescribed antibiotic is not the best treatment for severe cases. Scientists at the VA Salt Lake City Health Care System and University of Utah report that patients with a severe C. diff infection (CDI) were less likely to die when treated with the antibiotic vancomycin compared to the standard treatment of metronidazole.

The findings will be published online on Feb. 6, 2017 on the Journal of the American Medical Association (JAMA) Internal Medicine website.

C. diff does not cause illness outright. The bacterium produces two chemicals that are toxic to the human body. These toxins work in concert to irritate the cells of the Large intestinal lining producing the symptoms associated with the illness. Symptoms of CDI include watery diarrhea, fever, loss of appetite, nausea, and abdominal pain and tenderness. Severe cases are associated with inflammation of the colon.

Current guidelines primarily recommend two antibiotics metronidazole or vancomycin to treat CDI. While vancomycin was the original treatment, the medical community has favored metronidazole for the past few decades, because it is less expensive and will limit vancomycin resistance in other hospital-acquired infections. The guidelines are based on small clinical trials carried out about 30 years ago.

“For many years the two antibiotics were considered to be equivalent in their ability to cure C. diff and prevent recurrent disease,” says Stevens. “Our work and several other studies show that this isn’t always the case.” In the current issue of JAMA Internal Medicine, the research team looked at the effectiveness of the two drugs by comparing the risk of mortality after treatment with these two antibiotics.

The investigators conducted the largest study to date by examining the data from more than 10,000 patients treated for CDI through the US Department of Veterans Affairs healthcare system from 2005 to 2012. A severe case of CDI was defined as a patient with an elevated white blood cell count or serum creatinine within four days of the CDI diagnosis. A mild to moderate case of CDI was defined as a patient with normal white blood cell counts and creatinine levels. About 35 percent of cases in this study were considered severe.

Patients with a severe case of CDI had lower mortality rates when treated with vancomycin compared to metronidazole (15.3 percent versus 19.8 percent). The scientists calculated that only 25 patients with severe CDI would need to be treated with vancomycin to prevent one death. “That is a powerful, positive outcome for our patient’s well-being,” explains Stevens. She cautions that the researchers still do not understand how the choice of antibiotic affects mortality rates.

“Although antibiotics are one of the greatest miracles of modern medicine, there are still tremendous gaps in our knowledge about when and how to use them to give our patients the best health outcomes,” explains Michael Rubin, M.D., Ph.D., an associate professor in internal medicine and an investigator at the VA Salt Lake City Health Care System.

“This research shows that if providers choose vancomycin over metronidazole to treat patients with severe CDI, it should result in a lower risk of death for those critically ill patients,” said Rubin. This study showed that less than 15 percent of CDI patients, including severe cases, received vancomycin.

The study results did not show a difference in the rate of the illness returning following either antibiotic treatment whether the initial illness was mild to moderate or severe. Nor did it show a difference for the rate of death following either antibiotic treatment for mild to moderate CDI cases.

Stevens cautions that the study was observational in nature and does not prove cause and effect of the drug. In addition, the study focused on patients that were primarily men; however, past studies show that the C. diff treatment outcomes for men and women were similar.

According to Stevens, future work should balance the targeted application of vancomycin treatment, especially for severe CDI cases, with economic considerations and the consequences of antibiotic resistance. “The optimal way to move forward is to do decision analysis that allows us to weigh the pros and cons of the various treatment strategies,” she says.

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The research was funded by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development.

Ordering information is available on the brand website:

ZINPLAVA™ is indicated to reduce recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at a high risk for CDI recurrence.

ZINPLAVA is not indicated for the treatment of CDI.

ZINPLAVA is not an antibacterial drug.

ZINPLAVA should only be used in conjunction with antibacterial drug treatment of CDI.

Clifford McDonald, MD, Associate Director for Science in the Division of Healthcare Quality Promotion at the Centers for Disease Control and Prevention (CDC), chaired the conference. In his role at the CDC, McDonald’s at the forefront of efforts to prevent and treat the infection – one the CDC has declared among the most urgent drug-resistant threats that we currently face.

“It’s my firm belief that we are on the threshold of a new era in better diagnosis, treatment, and prevention approaches. At the CDC, we deal with statistics, but there are faces behind those numbers. At the heart of every infection is a patient who deserves our competence, our empathy, and our passion,” said McDonald.

One of those faces, Roy Poole, is a volunteer patient advocate for the C Diff Foundation. After retiring from a career in the Air Force, Poole led a healthy, active lifestyle as an avid outdoors-man in Colorado before antibiotics prescribed for a routine dental procedure set the stage for CDI. In the medical community, his symptoms were met with disbelief and inappropriate treatment.

“Three weeks after leaving the hospital, I walked into my (previous) primary care physician, and asked for an order to have a stool sample taken to determine if Toxins A or B were present. His response was, ‘Are you still having problems with that?’ Clearly, there is a need for more education about C. diff among physicians,” said Poole.

CDI is a formidable opponent. However, with the newly focused attention on discovering ways to disable the bacteria and cohesive public health approaches aimed at prevention, presenters from government, academia and industry offered five key reasons we can win the battle against C. diff:

Antibiotic stewardship efforts are gaining a foothold.
Statistics present a chilling picture: 453,000 new cases and an estimated 30,000 deaths each year. It’s likely that those numbers grossly underestimate the true impact of CDI, since it’s what we know from death certificate reporting.

However, we are seeing that rates may have peaked after a long plateau. Mark Wilcox, MD, Head of Microbiology at Leeds Teaching Hospital, Professor of Medical Microbiology at University of Leeds, and the lead on Clostridium difficile for Public Health England in the United Kingdom, has demonstrated a 70% reduction in cases in England in just 7 years. This was after a concerted effort that Wilcox spearheaded surrounding antibiotic stewardship, specifically addressing a reduction in unnecessary prescribing of fluoroquinolones and cephalosporin antibiotics.

Commonly prescribed antibiotics disrupt the protective microbiota (the normal bacteria of the gut) and leave it vulnerable for C. diff colonization. “There was a concerted effort that went beyond lip service and truly embraced the principles of improved surveillance, more accurate diagnostics, enhanced infection prevention measures to use antibiotics more wisely and to limit transmission and careful treatment,” said Wilcox.

High rates of CDI are always associated with the use of certain antibiotics: clindamycin, cephalosporin, and fluoroquinolones. Research has shown that lower respiratory tract infections and urinary tract infections account for more than 50% of all in-patient antibiotics use. But are these really necessary?

“We know that antibiotics are overused and misused across every healthcare setting. At least 30% of antibiotic prescriptions are unnecessary – and this equates to 47 million unnecessary antibiotic prescriptions per year written in doctors’ offices, hospital outpatient departments, and emergency departments. We have a lot of work to do, and CDC is actively working to reduce unnecessary antibiotic use,” said Arjun Srinivasan, MD at the CDC. “Stopping unnecessary antibiotics is the single most effective thing we can do to curb C. diff infections in the United States. This is something that we can do today.”

Srinivasan acknowledged that telling patients that they can’t have a prescription for an antibiotic might result in some pushback. “Patient satisfaction scores are a very real concern. When someone is sick and takes a day off work, they’re not leaving without a prescription – especially when the last provider wrote one for their same symptoms,” he said. “But this is a new day, and it’s up to the physician to educate their patients and stay strong.”

Hospitalists have access to accurate, inexpensive and quick diagnostic tests that can lead to targeted, effective treatment. This can arm the treating physician and patient with information that can put patients on a path to recovery without feeling like they are being dismissed.

Emerging guidance reflects important advances in research and development.

Most recently published in 2010, the Society for Healthcare Epidemiology of America (SHEA) and Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for C. diff are currently under review. This is critical because of the number of physicians still treating with metronidazole first, despite the fact that the largest randomized controlled clinical trial has shown that vancomycin is more effective.

“The past few years have ushered in a new age of understanding how and where C. diff colonizes, and the damaging toxins A and B that it produces.”

Considering that 25-30% of patients experience a CDI recurrence, it’s evident that metronidazole unnecessarily contributes to the failed treatment outcomes for patients. Metronidazole is less expensive, but has more side effects than oral vancomycin and is less effective in treating CDI.

Johnson provided an overview of the dramatic advances this space has seen in just the past few years.

Limitations of current guidelines include:
• No mention of fidaxomicin, a narrow-spectrum antibiotic, which in 2011 was the first medication approved in 25 years for the treatment of C. diff associated diarrhea
• Limited evidence for recommendations to treat severe, complicated CDI
• Limited evidence for recommendations on recurrent CDI
• Little mention of Fecal Microbiota Transplant (FMT)

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5. Patient advocacy and awareness efforts can alter the course of CDI.CDI survivors shared their experiences along their emotional journey – fear, disbelief, isolation, and depression. They also expressed gratitude at the validation, information and support they received from the patient advocacy community. Perhaps the greatest gift they have received is the empowerment to question their physicians about the necessity of antibiotics they have been prescribed in terms of risk of CDI.

“The hospital where I was treated initially seemed eager to have me leave. They offered no additional help. The C diff Foundation has been my greatest source of help. In turn, I feel I help myself cope best, when I help others to cope with the disease,” said Poole.

TO READ THIS ARTICLE IN ITS ENTIRETY AS PUBLISHED IN THE MD MAGAZINE

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Dale Gerding, MD, FACP, FIDSA, is Professor of Medicine at Loyola University Chicago, Research Physician at the Edward Hines Jr. VA Hospital. Additionally, Gerding is an infectious disease specialist and hospital epidemiologist, past president of the Society for Healthcare Epidemiology of America and past chair of the antibiotic resistance committee of SHEA. He is a fellow of the Infectious Diseases Society of America and past chair of the National and Global Public Health Committee and the Antibiotic Resistance Subcommittee of IDSA. His research interests include the epidemiology and prevention of Clostridium difficile, antimicrobial resistance, and antimicrobial distribution and kinetics.

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